Patients undergoing hemodialysis result in hyperphosphatemia. This can cause secondary hyperparathyroidism and promotes vascular calcification. To avoid these complications, serum phosphate (Pi) levels must be controlled by phosphate binders. Phosphate binders are a group of medications used to reduce the absorption of phosphates. It has been suggested that the sequestering of dietary phosphates in the stomach before they enter the small intestine and undergo absorption would be a beneficial attribute for a phosphate binder. There has been a progressive evolution of oral phosphate binders from aluminium, through calcium salts and on to newer agents such as sevelamer and lanthanum carbonate which are all dosed, on average, three times per day.
The three key elements in the management of elevated serum phosphate in CKD are: i) dietary phosphate restriction, ii) removal of phosphate from the systemic circulation by dialysis (hemodialysis) or peritoneal dialysis and iii) the use of phosphate binding agents to impede absorption of dietary phosphate from the GI tract (i.e., oral phosphate binders). Dietary phosphate restriction is impractical for many patients and it can be restricted only to a certain extent without risking protein malnutrition, particularly in elderly patients. Conventional 4-h, thrice-weekly hemodialysis removes approximately 1000 mg of phosphate per session, but this is generally insufficient to maintain phosphate levels within the recommended targets. Peritoneal dialysis removes slightly more than this when averaged over a week, but is still insufficient. Moreover, cost and patient acceptance issues further limit the usage of these modalities. Thus, around 90% of dialysis patients continue to need oral phosphate binders in an effort to control their phosphate levels.
In general, the ideal characteristics of an oral phosphate binder include: i) high affinity for binding phosphate which means low required dose (pill burden), ii) rapid phosphate binding regardless of ambient pH, iii) low solubility, iv) little to no systemic absorption, v) non-toxic and without side-effects, vi) solid oral dosage form, vii) palatability which encourages patient's compliance and viii) low cost.
Sevelamer is a polymeric amine that binds phosphate and is administered orally. It's a polyallylamine crosslinked with epichlorohydrin in which approximately forty percent of the amines are protonated. Sevelamer is hydrophilic and it exists as a hydrogel that can absorb approximately twenty times its weight in water, but is insoluble in most solvents including water.
Sevelamer main salt forms are the hydrochloride and the carbonate. Sevelamer hydrochloride was the first synthetic non-aluminum and calcium-free phosphate binder to become commercially available. It is an anion exchange resin consisting of a non-absorbed poly (allylamine hydrochloride) polymer. It contains multiple amines separated by one carbon from the polymer backbone. These amines become partially protonated in the intestine and interact with phosphate and other ions through ionic and hydrogen bonding. A more recent formulation of sevelamer consisting of sevelamer carbonate has been approved for use. This alternative sevelamer form appears to have equivalent ability to lower phosphorus serum concentration with that of sevelamer hydrochloride without affecting the serum bicarbonate concentration.
Sevelamer, unlike other phosphate binders, is able to correct hyperphosphatemia without promoting arterial calcification. A significant point to be noted is that end-stage renal disease patients restrict their fluid intake in order to control blood pressure and avoid heart failure. Furthermore, phosphate binders, due to their nature and their functionality are administrated in large doses several times per day. The size of the marketed tablets is large enough to prohibit their use by many patient categories such as elderly people and children, who could have difficulties swallowing them.
The most frequently used method for administering an active pharmaceutical ingredient to a patient are solid oral pharmaceutical dosage forms. Widely used oral medications are tablets and capsules. Nevertheless, many individuals have difficulties in swallowing. Elderly patients and children are usually unwilling, or unable, to swallow tablets and capsules. This leads to poor compliance and ineffective treatment of the patient. Additionally, such dosage forms are inconvenient for people that do not have access to water or a fluid.
In order to overcome said drawbacks and to improve compliance, lozenges, chewable, orally dispersible and sublingual dosage forms have been introduced. Some of the challenges in developing such dosage forms include taste-masking, mouth-feel, grittiness and manufacturing issues. Furthermore, packaging can be a critical aspect since they have to maintain low moisture content during storage. Another typical problem is their low hardness and, as a result, their inadequate friability causing inconvenience during the manufacturing and packaging procedure. Furthermore, a significant issue is the hydroscopicity of many of those products mainly due to the hydroscopicity of the active ingredients used.
However, until now, a fast dissolving composition in the above mentioned tablet forms comprising sevelamer or salts or derivatives thereof as the active pharmaceutical ingredient has not been proposed, probably because of its high hydroscopicity, bitter taste and swelling in the oral cavity, causing difficulties in manufacture and increase discomfort to patients leading to reduces compliance.
Various compositions and methods for preparing chewable tablets of various active ingredients have been proposed.
U.S. Pat. No. 7,029,699 B1 provide a chewable tablet containing Acetaminophen, a water-disintegratable and compressible carbohydrate and a binder.
U.S. Pat. No. 7,482,022 B1 discloses a palatable, chewable tablet comprising Cetirizine, a sweetener, a combination of a grape and vanilla flavouring and a cyclodextrin.
U.S. Pat. No. 5,629,013 B1 claims a chewable composition of calcium carbonate with aspartame, saccharin and 3-1-menthoxypropane-1,2-diol.
WO 95/05165 A1 discloses chewable tablets comprising hydrolysed gelatine as a flavour enhancer.
Therefore, there exists the need of a composition that will provide better patient compliance and ease of administration, comprising a phosphate binder such as sevelamer or salts or derivatives thereof as the active ingredient.